A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure (ASTRAAS)

A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor of Angiotensinogen Production Administered Subcutaneously for 12 Weeks to Hypertensive Patients With Uncontrolled Blood Pressure

The purpose of this study is to evaluate the effect of IONIS-AGT-LRx compared to placebo on seated automated office systolic blood pressure (SBP) from baseline to Study Day 85 in uncontrolled hypertensive participants on ≥ 3 antihypertensive medications and to evaluate the effect of IONIS-AGT-LRx on ambulatory blood pressure, seated automated office SBP, seated automated office diastolic blood pressure (DBP), and plasma angiotensinogen (AGT) at each scheduled visit in uncontrolled hypertensive participants on ≥ 3 antihypertensive medications.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: IONIS-AGT-LRx; Drug: Placebo

Detailed Description

This study will be a Phase 2, double-blind, randomized, placebo-controlled study in up to 150 participants. Participants will be randomized in a 2:1 ratio and will receive a once-weekly subcutaneous (SC) treatment with either IONIS-AGT-LRx or matching placebo. The length of participation in the study will be approximately 31 weeks, which includes an up to 6-week screening period, a 12-week treatment period, and a 13-week post-treatment period.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Ecogene-21
    • Saint-Jean-sur-Richelieu, Quebec, Canada, J3A 1J2
      • CardioVasc HR
• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Pinnacle Research Group
    • Birmingham, Alabama, United States, 35216
      • Achieve Clinical Research, LLC
    • Birmingham, Alabama, United States, 35205
      • Central Research Associates, Inc.
    • Pelham, Alabama, United States, 35124
      • Cahaba Research, Inc.
    • Sheffield, Alabama, United States, 35660
      • Syed Research Consultants Llc
  • Arkansas
    • Little Rock, Arkansas, United States, 72204
      • Cardiology and Medicine Clinic
  • California
    • Anaheim, California, United States, 92805
      • Advanced Research Center
    • Huntington Park, California, United States, 90255
      • National Research Institute - Huntington Park
    • La Mesa, California, United States, 91942
      • RESPIRE Research
    • Lincoln, California, United States, 95648
      • Clinical Trials Research
    • Montclair, California, United States, 91763
      • Catalina Research Institute
    • Van Nuys, California, United States, 91405
      • San Fernando Valley Health Institute
  • Colorado
    • Denver, Colorado, United States, 80246
      • Creekside Endocrine Associates, PC
  • Connecticut
    • Waterbury, Connecticut, United States, 06708
      • Chase Medical Research LLC
  • Florida
    • Cooper City, Florida, United States, 33024
      • ALL Medical Research, LLC
    • Crystal River, Florida, United States, 34429
      • Nature Coast Clinical Research - Crystal River
    • Jacksonville, Florida, United States, 32216
      • East Coast Institute for Research
    • Lake Worth, Florida, United States, 33467
      • Canvas Clinical Research
    • Miami, Florida, United States, 33155
      • Allied Biomedical Research Institute, Inc.
    • Miami Gardens, Florida, United States, 33169
      • AMPM Research Clinic
    • New Port Richey, Florida, United States, 34653
      • Advanced Research Institute Inc
    • Ocala, Florida, United States, 34471
      • Ocala Research Institute
    • Port Orange, Florida, United States, 32124
      • Progressive Medical Research
  • Georgia
    • Buford, Georgia, United States, 30519
      • Gwinnett Research Institute
    • Decatur, Georgia, United States, 30030
      • Sandhill Research, LLC
    • Marietta, Georgia, United States, 30060
      • Georgia Institute for Clinical Research
  • Illinois
    • Chicago, Illinois, United States, 60621
      • Eagle Clinical Research
    • Wauconda, Illinois, United States, 60084
      • Clinical Investigation Specialists, Inc. - Wauconda
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • The Research Group of Lexington, LLC
  • Louisiana
    • Slidell, Louisiana, United States, 70458
      • Louisiana Heart Center
    • West Monroe, Louisiana, United States, 71291
      • Clinical Trials of America, LLC - Monroe, LA
  • Michigan
    • Caro, Michigan, United States, 48723
      • BioPharm Clinical Research
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Palm Research Center, Inc.
  • New York
    • Brooklyn, New York, United States, 11235
      • NY Scientific
  • Ohio
    • Stow, Ohio, United States, 44224
      • Summit Research Group, LLC
  • Oklahoma
    • Edmond, Oklahoma, United States, 73013
      • Conrad Clinical Research
    • Oklahoma City, Oklahoma, United States, 73135
      • South Oklahoma Heart Research
  • South Dakota
    • Rapid City, South Dakota, United States, 57702
      • Health Concepts Research
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Research & Medicine, PLLC
    • Kingsport, Tennessee, United States, 37660
      • Holston Medical Group
  • Texas
    • Allen, Texas, United States, 75013
      • North Texas Research Associates
    • Houston, Texas, United States, 77040
      • Juno Research, LL
    • Hurst, Texas, United States, 76054
      • Protenium Clinical Research, LLC
    • Laredo, Texas, United States, 78041
      • Laguna Clinical Research Associates
  • Utah
    • Salt Lake City, Utah, United States, 84102
      • Kalo Clinical Research
  • Virginia
    • Manassas, Virginia, United States, 20110
      • Manassas Clinical Research Center
    • Norfolk, Virginia, United States, 23510
      • York Clinical Research LLC
    • Williamsburg, Virginia, United States, 23188
      • TPMG Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females aged 18-80 inclusive and weighing ≥ 50 kilograms (kg) at the time of informed consent
• Females: must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
• Males must be abstinent, surgically sterile or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective contraceptive method must be used
• Body mass index (BMI) ≤ 45.0 kilograms per square meter (kg/m^2)
• At screening, the participant must have been on a stable, maximally tolerated regimen (per Investigator judgement) of 3 or more antihypertensive medications for at least 1 month prior to screening and will be required to maintain this regimen throughout the study. The combination of antihypertensive medications must be in the following categories: a) angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), b) beta blocker: c) calcium channel blocker d) diuretic, e) alpha-1 blocker f) centrally acting sympatholytic agent or g) direct acting vasodilators (e.g. hydralazine)

Exclusion Criteria:

• Clinically significant abnormalities in screening laboratory results, medical history according to Investigator judgment
• History of secondary hypertension (HTN) including, but not limited to any of the following: renovascular HTN (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing's disease, pheochromocytoma, polycystic kidney disease, and drug-induced HTN

• The use of the following at time of screening and during the course of the study:

  • Other medications for the treatment of HTN (e.g., minoxidil, diazoxide, renin inhibitors)
  • Medications that may cause hyperkalemia unless on a stable dose at least 1 month prior to the screening visit and no known history of hyperkalemia per Investigator judgement
  • Use of oral anticoagulants, unless stable for 4 weeks prior to the first dose of study drug and regular monitoring must be performed per clinical practice during the study unless the participant is receiving vitamin K agonists. If the participant is receiving vitamin K antagonists (e.g., warfarin) international normalized ratio (INR) should be in therapeutic range, as established by the Investigator, for 4 weeks prior to the first dose
  • Chronic administration of NSAIDs or COX-2 inhibitors (except aspirin for cardiovascular disease provided the total daily dose does not exceed 325 mg)
• History of bleeding diathesis, coagulopathy, immune thrombocytopenic purpura (ITP), thrombotic cytopenic purpura (TTP), or any qualitative or quantitative platelet defect

• Unstable/underlying known cardiovascular disease defined as:

  • Any history of congestive heart failure (New York Heart Association [NYHA] Class III-IV)
  • Any history of previous myocardial infarction, coronary revascularization, unstable or stable angina pectoris ˂ 1 year prior to screening
  • Any hemodynamically unstable atrial or ventricular arrhythmias
  • Significant uncorrected valvular heart disease
  • Any history of stroke or transient ischemic attack < 1 year prior to screening
• A cardiac valve repair, cardiac device implantation, and/or a hospitalization for heart failure within 3 months of screening
• Participant works nighttime shifts (e.g., 11 PM to 7 AM)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IONIS-AGT-LRx; Multiple doses of IONIS-AGT-LRx will be administered subcutaneously once-weekly for 12 weeks.	Drug: IONIS-AGT-LRx; Multiple doses of IONIS-AGT-LRx will be administered by SC injection.; Other Names: ISIS 757456
Placebo Comparator: Placebo; IONIS-AGT-LRx-matching placebo will be administered subcutaneously once-weekly for 12 weeks.	Drug: Placebo; IONIS-AGT-LRx-matching placebo will be administered by SC injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Seated Automated Office Systolic Blood Pressure (SBP) from Baseline to Study Day 85	Baseline to Day 85

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline in plasma AGT to each scheduled, post-baseline visit	Baseline up to Day 169
Change from Baseline to Study Day 85 in 24-hour mean SBP measured by ambulatory blood pressure monitoring (ABPM)	Baseline to Day 85
Change from Baseline to Study Day 85 in 24-hour mean Diastolic Blood Pressure (DBP) measured by ABPM	Baseline up to Day 85
Percentage of participants reaching the goals of seated automated office seated SBP ≤ 140 mmHg, DBP ≤ 90 mmHg, and both during the study (excluding participants with a baseline SBP of ≤ 140 mmHg)	Up to Day 169
Percentage of participants reaching the goals of automated office seated SBP ≤ 130 mmHg, DBP ≤ 80 mmHg, and both during the study	Baseline up to Day 169
Change from Baseline on seated automated office SBP to each scheduled, post-Baseline visit	Baseline up to Day 169
Change from Baseline on seated automated office DBP to each scheduled, post-Baseline visit	Baseline up to Day 169

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2021
• Primary Completion (Actual): September 15, 2022
• Study Completion (Actual): September 20, 2022

Study Registration Dates

• First Submitted: January 14, 2021
• First Submitted That Met QC Criteria: January 14, 2021
• First Posted (Actual): January 19, 2021

Study Record Updates

• Last Update Posted (Estimate): February 27, 2023
• Last Update Submitted That Met QC Criteria: February 18, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Hypertension; Hypertensive; Blood Pressure; AGT; Angiotensinogen
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension
• Other Study ID Numbers: ISIS 757456-CS4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No